Sepsis due to Bacillus anthracis is highly lethal and a major bioterrorism threat today. Lethal toxin (LeTx) released by B. anthracis and comprised of protective antigen (PA) and lethal factor (LF) is central to this disease. In a conventional Fisher 344 rat model of anthrax sepsis employing a intravenous bolus of LeTx, administration of PA-mAb prior to or at the time of LeTx injection, but not later, increased survival. However, this model does not simulate the continuous release of LeTx that occurs during actual infection and the rapid death (i.e. 1.5 h) induced by bolus injection of LeTx may have negated the possibility of observing therapeutic benefit from later mAb treatment. Therefore we investigated PA-mAb or placebo (nonspecific mAb) administered in rats (n=185) at the time of (0 h) or 3, 6, 9, or 12 h after the start of a 24 h infusion of LeTx. Mean time to death was similar (p=ns) in placebo animals independent of treatment time (median 15 h, range 9 to 152 h, p=ns). At each treatment time, survival rates (%) were greater with PA-mAb compared to placebo although these differences decreased with the latest treatments (100 vs 67, p=0.001 at 0 h; 90 vs 42, p=0.01 at 3 h; 100 vs 56, p=0.001 at 6 h; 73 vs 56, p=0.2 at 9 h; and 79 vs 53, p=0.2 at 12 h). In rats receiving a 24 h LeTx infusion in which lethality was high but later than in conventional anthrax models, PA-mAb given up to 6 h after initial LeTx exposure was very protective and given 9 and 12 h after caused beneficial trends in outcome. Clinically, PA-mAb may reduce morbidity or mortality due to LeTx release even if administered after patients present with anthrax sepsis.